Showing papers by "ACADIA Pharmaceuticals Inc. published in 2002"

Discovery of an Ectopic Activation Site on the M1Muscarinic Receptor

Abstract: Receptors have well-conserved regions that are recognized and activated by hormones and neurotransmitters. Most drugs bind to these sites and mimic or block the action of the native ligands. Using a high-throughput functional screen, we identified a potent and selective M 1 muscarinic receptor agonist from a novel structural class. Using a series of chimeric receptors, we demonstrated that this ligand activates the receptor through a region that is not conserved among receptor subtypes, explaining its unprecedented selectivity. This region of the receptor is distinct from the conserved region that is recognized by traditional ligands. The finding that receptors for small-molecule transmitters can have multiple, structurally distinct activation sites has broad implications for the study of receptor structure/function and the potential for the discovery of novel ligands with high selectivity.

Discovery of the first nonpeptide agonist of the GPR14/Urotensin-II receptor: 3-(4-Chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one (AC-7954)

Abstract: A functional cell-based screen identified 3-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)isochroman-1-one hydrochloride (AC-7954, 1) as a nonpeptidic agonist of the urotensin-II receptor. Racemic 1 had an EC50 of 300 nM at the human UII receptor and was highly selective. Testing of the enantiopure (+)- and (-)- 1 revealed that the UII receptor activity of racemic 1 resides primarily in (+)-1. Being a selective nonpeptidic druglike UII receptor agonist, (+)-1 will be useful as a pharmacological research tool and a potential drug lead.

Spiroazacyclic compounds as monoamine receptor modulators

Abstract: The present invention relates to spiroazacyclic compounds as monoamine receptor modulators; compositions comprising the same; methods of inhibiting an activity of a monoamine receptor with said compounds; methods of treating a disease condition associated with a monoamine receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

Benzimidazolidinone derivatives as muscarinic agents

Abstract: Benzimidazolidinone derivative compounds, which increase acetylcholine signaling or effect in the brain, and highly selective muscarinic agonists, particularly for the M1 and/or M4 receptor subtypes, pharmaceutical compositions comprising the same, as well as methods of treating psychosis using these compounds are disclosed.

Homologous mutations near the junction of the sixth transmembrane domain and the third extracellular loop lead to constitutive activity and enhanced agonist affinity at all muscarinic receptor subtypes.

Abstract: Previous studies have found that a mutation near the junction of the sixth transmembrane domain (TM6) and the third extracellular loop of the M5 muscarinic receptor leads to constitutive activation and enhanced agonist affinity for the mutated receptor. These results were consistent with the extended ternary complex model, which predicts a correlation between agonist affinity and constitutive activity. We have introduced the homologous mutation into all five subtypes of the highly conserved muscarinic receptor family; SerThr→TyrPro was introduced into M1 and M5, and AsnThr→TyrPro was introduced into M2, M3, and M4. In binding assays, these mutations produced increases in affinities toward acetylcholine and carbachol that ranged from 5-fold at the M2 receptor to 15- to 20-fold at M1, M3, and M4, to 40-fold at M5. In functional assays, all five mutant receptors exhibited constitutive activity, at levels ranging between 30 and 80% of the maximal response elicited by carbachol. In every case, the muscarinic antagonist atropine inhibited this constitutive activity with high affinity. Thus, despite differences in effector coupling and in wild-type sequence at the mutation site, all five subtypes were activated by this mutation at the top of TM6. Previous studies of the M5 subtype have indicated that TM6 is a ligand-dependent switch that sets the activation state of the receptor. Based on the results of the present study, it is possible that TM6 represents a general switch for the activation of the muscarinic receptor family.

Tetrahydroquinoline analogues as muscarinic agonists

Abstract: The present invention relates to tetrahydroquinoline compounds as muscarinic receptor agonists; compositions comprising the same; methods of inhibiting an activity of a muscarinic receptor with said compounds; methods of treating a disease condition associated with a muscarinic receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

Dissection of the cytoplasmic domains of cytokine receptors involved in STAT and Ras dependent proliferation

Abstract: Cytokine receptors have different signaling requirements which ultimately lead to various physiological responses. In an effort to precisely characterize the molecular determinants involved in the proliferative response mediated by cytokines, we examine dose-dependent proliferation of the βc (GM-CSF, IL-3, IL-5) and homodimeric (G-CSF, TPO) cytokine receptors. Here we report that all cytokine receptors tested activate mostly STAT3 and STAT5. While STAT3 had a positive effect on βc cytokine receptor dependent proliferation, STAT5 was strongly inhibitory. Similarly, G-CSF and TPO lead to activation of STAT3 and STAT5 but, unlike the βc cytokine receptors, both stimulated cellular growth. On the other hand, Ras activation was necessary for all receptor mediated proliferation with the exception of G-CSF R. Truncated mutants of the receptors intracellular domains were used to delineate the functional domains involved in JAK/STAT and Ras activation linked to cellular growth. For instance, we revealed a critical role for the specific alpha subunit of the βc receptors in triggering receptor activation, STAT3 stimulation and proliferation, while Ras activation originates from the distal intracellular portion of the βc subunit. Finally, we showed that proximal STAT activation is the triggering event of G-CSF and TPO receptor function.

Regioselective acylation of 1-hydroxypyrazoles via metalated intermediates

Abstract: A range of C-4 and C-5 acylated 1-benzyloxypyrazoles (7a–e) and (4) have been prepared via Pd(0) catalysed cross-coupling between acid chlorides and 1-benzyloxy-4-(tributylstannyl)pyrazole (8) or 1-benzyloxypyrazol-5-ylzinc chloride. 3-Acylated 2-(4-methoxybenzyl)-2H-pyrazole 1-oxides (15a–f) were formed by reaction between the 3-magnesiated 2H-pyrazole 1-oxide (14) and acid chlorides. The benzyl group of 4 and 7a and the 4-methoxybenzyl (PMB) group of 15a were removed by treatment with conc. HCl or TFA in the presence of water, furnishing the corresponding C-acylated 1-hydroxypyrazoles.

Nad-299 antagonises 5-HT-stimulated and spiperone-inhibited [35S]GTPgammaS binding in cloned 5-HT1A receptors.

Abstract: In Chinese Hamster Ovary (CHO) cells expressing cloned human 5-hydroxy-tryptamine1A (5-HT1A) receptors, (R)-3-N,N-dicyclobutylamino-8-fluoro-[6-3H]-3,4-dihydro-2H-1-benzopyran-5-carboxamide ([3H]NAD-299) exhibited high affinity (Kd = 0.16 nM) and labeled 34% more receptors than 8-hydroxy-2-([2,3-3H]di-n-propylamino)tetralin ([3H]8-OH-DPAT). NAD-299 behaved as a silent antagonist in [35S]GTPγS binding similar to N-tert-butyl-3-(4-(2-methoxyphenyl)-piperazin-1-yl)-2-phenylpropanamide (WAY-100635) and (S)-5-fluoro-8-hydroxy-2-(di-n-propylamino)tetralin ((S)UH-301). 5-HT and 5-carboxamidotryptamine (5-CT) stimulated [35S]GTPγS binding 2.5-fold while spiperone and methiothepin inhibited [35S]GTPγS binding 1.4-fold. Furthermore, NAD-299 antagonised both the 5-HT stimulated and the spiperone inhibited [35S]GTPγS binding to basal levels. The KiL/KiH ratios for spiperone (0.66), methiothepin (0.39), WAY-100635 (0.32), (S)UH-301 (0.94), NAD-299 (1.29), NAN-190 (1.23), (S)pindolol (5.85), ipsapirone (13.1), ...

Chemical genomics: massively parallel technologies for rapid lead identification and target validation

Abstract: Chemical genomics is a new research paradigm with importantapplications in drug discovery It links genomic targets withsmall-molecule chemistries thereby allowing for efficient targetvalidation and lead compound identification ACADIA'schemical-genomics platform consists of a large and diverse small-moleculelibrary (800,000), a reference drug library (2,000), druggablegenomic targets (>300) and a cell-based functional assaytechnology (R-SATTM; Receptor Selection and AmplificationTechnology) that allows for ultra-high throughput screening(>500,000 data points/week) as well as high throughputpharmacology and profiling over a wide range of targets Twoexamples are presented that illustrate the success of ourchemical-genomics approach: (i) The validation of inverse agonismat serotonin 5-HT2A receptors as an antipsychotic mechanismand the subsequent discovery of potent and selectively acting 5-HT2A inverse agonists, currently in preclinical development,and (ii) the discovery of the first ectopically binding subtype-selective muscarinic m1 agonist

Clinical indications for genotyping polymorphic variants of G-protein coupled receptors

Abstract: The invention provides compositions and methods for screening individuals for the presence of G-protein coupled receptor (GPCR) variants. The compositions and methods are useful for determining clinical outcome of drug therapy or for tailoring drug therapy for the individual based upon the presence or absence of one or more GPCR variants in the subject.